Alzheimer?s disease (AD) is characterized by a progressive decline in memory and cognition, with concomitant alterations in behavior and personality. AD represents a leading cause of death and disability, particularly for individuals over 65 years of age. Current medications for treatment of AD have limited effectiveness. Due to its progressive nature, it is thought that disease processes are initiated well before the onset of clinical symptoms. Thus, in order to define new targets and treatment strategies, it is essential to better understand the physiological functions of proteins linked to AD. Amyloid precursor protein (APP), is well- recognized to serve as the source of the ?-amyloid peptide (A?) that becomes deposited in amyloid plaques, a key histopathological hallmark of the disease. The endogenous functions of APP remain incompletely understood, yet mutations in either APP or cleaving enzymes responsible for generating A? from APP are known to cause familial forms of AD (FAD) with early onset. Thus, it is important to understand what APP may be doing prior to its cleavage. Synaptic dysfunction is thought to be one of the earliest events in AD progression, and consequently the presence of APP at synapses likely foretells the critical functions that are lost in AD due to its excessive and/or dysfunctional processing. In accord with a role in synaptic function, recent studies indicate that APP and APP-like proteins interact with the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) to enhance receptor surface expression. NMDARs have unique features that enable them to play central roles in various forms of synaptic plasticity that are thought to underlie learning and memory, as well as in neuronal development and neurodegeneration. Given the pivotal role of these receptors in these processes, which are all arguably relevant to AD, a fundamental understanding of the properties APP and APP-family members endow upon NMDAR signaling is essential in order to decode the role of this protein in normal physiology and in AD. Indeed, dysfunctional synapse to nucleus signaling may be prevalent in AD. Based on preliminary data, we believe that a specific region within APP, associated with FAD-linked mutations, is critical for the ability of APP, and its family members, to not only regulate NMDARs, but also for NMDARs to initiate downstream signaling. Aim 1 will biochemically examine the properties of this region and test the impact of FAD-linked mutations within APP on these properties using in vitro and cellular assays. Aim 2 will use electrophysiological techniques to examine whether APP and its family members regulate NMDAR function and the ability of FAD-linked mutations within APP to alter NMDAR activity. Aim 3 will use imaging-based cellular assays to examine whether APP and its family members control downstream NMDAR-mediated signaling to the cell nucleus and whether FAD-linked mutations in APP alters the strength of NMDAR-mediated nuclear signaling. Collectively, these studies will reveal a new pathway contributing to the endogenous regulation of NMDARs, which may underlie dysfunctional signaling in AD.